Alternative titles; symbols
SNOMEDCT: 15346004; ORPHA: 425; DO: 0080957;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q31.1 | HDL deficiency, familial, 1 | 604091 | Autosomal dominant | 3 | ABCA1 | 600046 |
A number sign (#) is used with this entry because of evidence that primary hypoalphalipoproteinemia-1 is caused by heterozygous mutation in the ABC1 gene (ABCA1; 600046) on chromosome 9q31, which is also the site of mutations causing Tangier disease (205400).
Twenty to 30% of early familial coronary heart disease (CHD) is ascribed to hypoalphalipoproteinemia, or high density lipoprotein deficiency. Although not initially recognized as a predisposing dyslipidemia, extensive epidemiologic work has implicated low high-density lipoprotein cholesterol (HDLC) levels in increased risk of cardiovascular disease, and low HDLC is considered to be a true dyslipidemic syndrome (Warnick and Wood, 1995).
Genetic Heterogeneity of Primary Hypoalphalipoproteinemia
Primary hypoalphalipoproteinemia-2 (618463) and intermediate primary hypoalphalipoproteinemia-2 (619836) are caused by mutation in the APOA1 gene (107680) on chromosome 11q23.
As in Tangier disease, an autosomal recessive disorder, the dominantly inherited disorder familial hypoalphalipoproteinemia shows a reduction in cellular cholesterol efflux (Marcil et al., 1999).
Clee et al. (2000) examined the phenotypes of 77 individuals heterozygous for mutations in the ABC1 gene. Heterozygotes had an approximately 40 to 45% decrease in HDL cholesterol (HDL-C) and apo-AI and a mild (approximately 10%) decrease in apo-AII compared with unaffected family members. Mean triglycerides were increased by approximately 40% in heterozygotes compared with unaffected family members. There was no significant decrease in total cholesterol or LDL cholesterol in heterozygotes. Symptomatic vascular disease was over 3 times as frequent in adult heterozygotes as in unaffected family members. The mean age of CAD onset was on average a decade earlier in heterozygotes compared to the unaffected controls. Age is an important modifier of the phenotype in heterozygotes, as a significantly larger percentage of individuals aged 30 to 70 years had HDL-C less than the fifth percentile compared to those younger than 30 years (p = 0.004).
After demonstrating mutations in the ABC1 gene in patients with Tangier disease, Brooks-Wilson et al. (1999) studied 4 French Canadian families with familial hypoalphalipoproteinemia. Linkage analysis revealed a maximum lod score of 9.67 at a recombination fraction of 0.0 at D9S277, the region to which Tangier disease had been mapped. These 2 diseases had hitherto been considered distinct, with different clinical and biochemical characteristics.
In affected members of French Canadian families with hypoalphalipoproteinemia, Brooks-Wilson et al. (1999) identified heterozygous mutations in the ABC1 gene (600046.0001-600046.0004). One of the families had previously been studied by Marcil et al. (1995).
Brooks-Wilson, A., Marcil, M., Clee, S. M., Zhang, L.-H., Roomp, K., van Dam, M., Yu, L., Brewer, C., Collins, J. A., Molhuizen, H. O. F., Loubser, O., Ouelette, B. F. F., and 14 others. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nature Genet. 22: 336-345, 1999. [PubMed: 10431236] [Full Text: https://doi.org/10.1038/11905]
Clee, S. M., Kastelein, J. J. P., van Dam, M., Marcil, M., Roomp, K., Zwarts, K. Y., Collins, J. A., Roelants, R., Tamasawa, N., Stulc, T., Suda, T., Ceska, R., Boucher, B., Rondeau, C., DeSouich, C., Brooks-Wilson, A., Molhuizen, H. O. F., Frohlich, J., Genest, J., Jr., Hayden, M. R. Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J. Clin. Invest. 106: 1263-1270, 2000. [PubMed: 11086027] [Full Text: https://doi.org/10.1172/JCI10727]
Marcil, M., Boucher, B., Krimbou, L., Solymoss, B. C., Davignon, J., Frohlich, J., Genest, J., Jr. Severe familial HDL deficiency in French-Canadian kindreds: clinical, biochemical, and molecular characterization. Arterioscler. Thromb. Vasc. Biol. 15: 1015-1024, 1995. [PubMed: 7627690] [Full Text: https://doi.org/10.1161/01.atv.15.8.1015]
Marcil, M., Yu, L., Krimbou, L., Boucher, B., Oram, J. F., Cohn, J. S., Genest, J., Jr. Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency. Arterioscler. Thromb. Vasc. Biol. 19: 159-169, 1999. [PubMed: 9888879] [Full Text: https://doi.org/10.1161/01.atv.19.1.159]
Warnick, G. R., Wood, P. D. National cholesterol education program recommendations for measurement of high-density lipoprotein cholesterol: executive summary. Clin. Chem. 41: 1427-1433, 1995. [PubMed: 7586512]